Stem cells are cells that are capable of self-renewal through mitotic cell division, and differentiation into a diverse range of specialized cell types. Hence, stem cells hold considerable promise for use in human therapy, for example in regenerative medicine and tissue replacement after injury or disease. Existing stem cell therapies include bone marrow transplants that are used to treat leukemia, while future uses of stem cell therapy are envisaged in the treatment of other cancers, Parkinson's disease, spinal cord injuries, amyotrophic lateral sclerosis, multiple sclerosis, and muscle damage.
Various types of stem cells are known. Embryonic stem cells (ESC) are derived from embryonic tissue, typically from the epiblast tissue of the inner cell mass (ICM) of a blastocyst or earlier morula stage embryos. Embryonic stem cells are pluripotent. Hence, during development, ESCs are capable of giving rise to all derivatives of the three primary germ layers (the ectoderm, endoderm and mesoderm) and develop into each of the various cell types of the adult body when provided with the requisite stimulus for a particular cell type. The pluripotency of ESCs is due to a core regulatory network of transcription factors (including OCT-4, Nanog and SOX2) that ensures the suppression of genes leading to differentiation. If injected into the human body without providing the specific signals for correct differentiation into the correct cell type, the ESCs will differentiate into many different cell types and cause teratoma.
Another type of stem cell is induced pluripotent stem cell (IPSC). IPSCs are a type of pluripotent stem cells that are artificially derived from a non-pluripotent cell, for example an adult somatic cell, by inducing expression of certain genes. It is believed that IPSCs are identical to natural pluripotent stem cells, such as ESCs, in many aspects including the expression of certain stem cell genes and proteins, chromatin methylation patterns, doubling time, embryoid body formation, teratoma formation, viable chimera formation, potency and differentiability. Typically, IPSCs are produced by transfection of certain stem cell-associated genes (for example OCT-3/4 and SOX2) into non-pluripotent cells through the use of viral vectors, such as retroviruses.
Yet another type of stem cell is cancer stem cell (CSC). CSCs are found within tumors or hematological cancers, and have characteristics associated with normal stem cells, specifically the ability to undergo self-renewal and differentiate into a diverse range of cell types. However, the tight metabolic control under which normal stem cells divide is lost in CSCs. Hence, CSCs are tumorigenic (tumor-forming), and are believed to persist in tumors as a distinct population causing relapse and metastasis by giving rise to new tumors. CSCs are also known to be resistant to apoptosis and chemotherapy, the latter due to the presence of ATP-binding cassette transporters, which remove drugs from the cell.
In cell therapy, the self-renewal and pluripotent properties of stem cells such as ESCs and IPSCs are useful in providing specific types of differentiated cells that are transplanted into a patient in order to treat a particular disease or injury. However, the self-renewal property of such stem cells is also associated with tumorigenicity. Hence, while the differentiated cells that are transplanted into the patient are not known to be tumorigenic, there is a risk of transplantation of residual populations of undifferentiated stem cells that can result in teratoma formation and functional failure of the graft. Attempts to address this problem include the generation of ESCs that express a suicide gene that renders cells sensitive to administration of the anti-viral drug ganciclovir. However, such a strategy eliminates all cells of the graft in response to ganciclovir, which not only negates any benefit from the transplant procedure, but also results in additional intervention being necessary.
Furthermore, differentiated cells can potentially undergo dedifferentiation post-transplantation. Dedifferentiation is a cellular process where a partially or terminally differentiated cell reverts to an undifferentiated state.
There is a need to provide compounds, compositions and methods that overcome or at least ameliorate one or more of the disadvantages described above.
There is a need to provide compounds, compositions and methods for use in cell therapy, particularly to prevent teratoma formation.
There is a need to provide compounds, compositions and methods that selectively remove undifferentiated or dedifferentiated stem cells prior to or post transplantation in cell therapy.
There is a need to provide compounds, compositions and methods that specifically remove CSCs to treat and improve survival and quality of life of cancer patients, particularly patients suffering from metastatic forms of cancer.
There is a need to provide compounds that selectively remove undifferentiated or dedifferentiated stem cells, and that can be produced in large quantities in a simple and cost-effective manner.